Heat-reduction methods and systems related to microfluidic devices

ABSTRACT

A system and method for preventing or reducing unwanted heat in a microfluidic of the device while generating heat in selected regions of the device. In one example, current is supplied to a heating element through electric leads, wherein the leads are designed so that the current density in the leads is substantially lower than the current density in the heating element. This maybe accomplished using conductive leads which have a cross-sectional area which is substantially greater than the cross-sectional area of the heating element. In another example, unwanted heat in the microfluidic complex is reduced by thermally isolating the electric leads from the microfluidic complex. This maybe accomplished by running each lead directly away from the microfluidic complex, through a thermally isolating substrate. After the leads pass through the thermally isolating substrate, they are then routed to the current source. Thus, the thermally isolating substrate substantially blocks the transfer of heat from the leads to the microfluidic complex. In another example, unwanted heat is removed from selected regions of the microfluidic complex using one or more cooling devices. One or more Peltier cooling devices may be attached to a substrate to remove heat generated by heating elements and/or other electronic circuitry.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims the benefit of priorityof U.S. application Ser. No. 12/750,471, filed Mar. 30, 2010, which is acontinuation of U.S. application Ser. No. 12/032,631, filed Feb. 15,2008, which is a continuation of U.S. application Ser. No. 10/778,598,filed Feb. 17, 2004, now U.S. Pat. No. 7,332,130, which is acontinuation of U.S. application Ser. No. 09/783,225, filed Feb. 14,2001, now U.S. Pat. No. 6,692,700, the entire contents of which arehereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to microfluidic devices, and moreparticularly to heat management in such devices.

2. Description of the Related Art

Microfluidic devices are known. For example, U.S. Pat. No. 6,130,098(“the '098 patent”) (the contents of which are incorporated herein intheir entirety by reference) discloses microfluidic devices that includemicrodroplet channels for transporting fluid droplets through a fluidprocessing system. The system includes a variety of microscalecomponents for processing the fluid droplets, including micro-reactionchambers, electrophoresis modules, and detectors (such as radiationdetectors). In some embodiments, the devices also include air chambersto internally generate air pressure to automatically withdraw a measuredvolume of fluid from an input port.

Typically, these elements are microfabricated from silicon, glass,ceramic, plastic, and/or quartz substrates. The various fluid-processingcomponents are linked by microchannels, through which the fluid dropletsflow under the control of a fluid propulsion mechanism. If the substrateis formed from silicon, electronic components may be fabricated on thesame substrate, allowing sensors and controlling circuitry to beincorporated in the same device. Since all of the components are madeusing conventional photolithographic techniques, multi-component devicescan be readily assembled into complex, integrated systems.

Microfluidic devices use heating elements to accomplish a variety oftasks. For example, U.S. Pat. No. 6,130,098 discloses devices that useheating elements to automatically withdraw a measured volume of fluidfrom a fluid input port. Liquid placed into a fluid port flows into achannel, past a chamber connected to the side of the channel, and stopsat a hydrophobic patch on the wall of the channel. The chamber is thenheated, causing pressure to build up. Once the pressure reaches aparticular threshold, a microdroplet splits from the rest of the liquid,and is pushed over the hydrophobic patch and down the channel forfurther processing.

Heating elements can also be used to move such a measured microfluidicdroplet through an etched channel. This can be accomplished using aheat-controlled pressure chamber as described in the '098 patent. Fluidmovement can also be performed using a series of heaters to generatethermal gradients to change the interfacial tension at the front or backof the droplets, thereby generating a pressure difference across thedroplet. For example, a droplet can be propelled forward by heating theback interface. The local increase in temperature reduces the surfacetension on the back surface of the droplet and decreases the interfacialpressure difference. The decreased pressure difference corresponds to anincrease in the local internal pressure on that end of the droplet. Thetwo droplet interfaces (front and back) are no longer in equilibrium,and the pressure difference propels the droplet forward. Forward motioncan be maintained by continuing to heat the droplet at the rear surfacewith successive heaters along the channel (see FIG. 5 of U.S. Pat. No.6,130,098), while heating the opposite surface can be used to reversethe motion of the droplet.

Other heater elements may be used to control the temperature in reactionchambers, for example, to perform PCR. Others may be used to manipulatevalves made of meltable material (such as wax or solder) as described inU.S. Pat. No. 6,048,734.

All such heater elements, when heating a particular region of amicrofluidic device, tend to generate unwanted heat in other regions ofthe device. Such unwanted heat may adversely affect operation of themicrofluidic devices. For example, too much heat can adversely affectthe properties of a liquid or gas being processed.

SUMMARY OF THE INVENTION

The invention relates to a system and method for preventing or reducingunwanted heat in a microfluidic device while generating heat in selectedregions of the device.

In one aspect, the invention involves supplying current to a heatingelement through electric leads, wherein the leads are designed so thatthe current density in the leads is substantially lower than the currentdensity in the heating element. In a preferred embodiment, this isaccomplished using conductive leads which have a cross-sectional areawhich is substantially greater than the cross-sectional area of theheating element.

In another aspect, the invention involves reducing the amount ofunwanted heat in the microfluidic complex by thermally isolating theelectric leads from the microfluidic complex. In a preferred embodiment,this is accomplished by running each lead directly away from themicrofluidic complex, through a thermally isolating substrate. Afterpassing through the thermally isolating substrate, the leads are thenrouted to the current source. Thus, the thermally isolating substratesubstantially blocks the transfer of heat from the leads to themicrofluidic complex.

In another aspect, the invention involves removing unwanted heat fromselected regions of the microfluidic complex using one or more coolingdevices. In a preferred embodiment, one or more Peltier cooling devicesare attached to a substrate to remove heat generated by heating elementsand/or other electronic circuitry.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an expanded view of a microfluidic device as is known in theart.

FIG. 2 shows a top-down view of the device in FIG. 1, assembled.

FIG. 3 shows a cross-sectional end view of the device in FIG. 2.

FIG. 4 shows a cross-sectional side view of the device in FIG. 2.

FIG. 5 shows a top-down view of a device comprising a preferredembodiment of the present invention.

FIG. 6 shows a cross-sectional end view of the device in FIG. 5.

FIG. 7 shows a cross-sectional side view of the device in FIG. 5.

FIG. 8 depicts the device in FIG. 3, with a Peltier device attached tothe lower substrate.

FIG. 9 depicts the device in FIG. 4, with a Peltier device attached tothe upper substrate.

FIG. 10 depicts the device in FIG. 5, with multiple Peltier devicesattached to the lower substrate.

FIG. 11 depicts a cross-sectional end view of the device in FIG. 10.

FIG. 12 depicts a cross-sectional side view of the device in FIG. 10.

FIG. 13 depicts a top-down view of a device comprising a furtherpreferred embodiment of the present invention.

FIG. 14 depicts a cross-sectional end view of the device in FIG. 13.

FIG. 15 depicts a cross-sectional side view of the device in FIG. 13.

FIG. 16 depicts a top-down view of a device comprising a furtherpreferred embodiment of the present invention.

FIG. 17 depicts a cylinder of substrate material comprising wires thatrun parallel to the axis of the cylinder and that are spacedcross-sectionally as the vertical leads are desired to be spaced in thesubstrate.

FIG. 18 depicts a lead-gridded substrate formed by slicing the cylinderdepicted in FIG. 17 into a cross-section of the desired thickness.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates to microfluidic devices, and inparticular, heat management in such devices.

Microfluidic devices typically include micromachined fluid networks inan integrated analysis system. Fluid samples and reagents are broughtinto the device through entry ports and transported through channels toa reaction chamber, such as a thermally controlled reactor where mixingand reactions (e.g., restriction enzyme digestion or nucleic acidamplification) occur. The biochemical products may then be moved, forexample, to an electrophoresis module, where migration data is collectedby a detector and transmitted to a recording instrument. The fluidic andelectronic components are preferably designed to be fully compatible infunction and construction with the biological reactions and reagents.

There are many formats, materials, and size scales for constructing suchintegrated micro-fluidic systems. FIG. 1 shows an expanded view of asimple microfluidic device, which will be used to illustrate some of theheat management techniques of the present invention. The device includesan upper substrate 120, which is bonded to a lower substrate 127 to forma fluid network (see FIGS. 2-4).

The upper substrate 120 depicted in FIG. 1 is preferably formed of glassand has a microfluidic complex 110 in its bottom surface 112. Thoseskilled in the art will recognize that substrates composed of silicon,glass, ceramics, plastic, and/or quartz are all acceptable in thecontext of the present invention.

Microfluidic complex 110 includes a plurality of chambers connected by anetwork of microchannels. The number of chambers and channels, as wellas the overall topology of the microfluidic complex, will depend uponthe particular application which the microfluidic device is designed toperform. However, FIG. 1 depicts a simple microfluidic complex forpurposes of illustrating the heat management techniques of the presentinvention, and is not intended to depict a microfluidic complex for anyparticular application.

The channels and chambers of the microfluidic complex are etched in thebottom surface 112 of the glass substrate 120 using knownphotolithographic techniques. More specifically, transparent templatesor masks containing opaque designs are used to photo-define objects onthe surface of the substrate. The patterns on the templates aregenerated with computer-aided-design programs and can delineatestructures with line-widths of less than one micron. Once a template isgenerated, it can be used almost indefinitely to produce identicalreplicate structures. Consequently, even extremely complex microfluidiccomplexes can be reproduced in mass quantities and at low incrementalunit cost.

The lower substrate 127 includes a glass base 130 and an oxide layer150. Within oxide layer 150, resistive heaters 140 and electric leads160 are formed. The leads 160 connect to terminals 170 which are exposedat the edge of the substrate to permit electrical connection to anexternal voltage source (not shown) that controls the heaters. Morespecifically, to activate a heater 140, a voltage is applied across apair of terminals 170 to supply current through leads 160 and heater140, thereby heating the resistive heater element 140. However, sincethe same current passes through leads 160, these leads are also heated.

Metal heater elements 140 are positioned so that, when the upper andlower substrates are bonded together, the heaters reside directlybeneath the fluid chambers of the upper substrate so as to be able toheat the contents of the microchambers. The silicon oxide layer 150prevents the heating elements 140 from directly contacting with fluid inthe microfluidic complex 110.

The oxide layer 150, heating elements 140, and resistive leads 160 arefabricated using well-known photolithographic techniques, such as thoseused to etch microfluidic complex 110.

FIG. 2 is a top-down view of the device in FIG. 1. In this figure, uppersubstrate 120 is shown atop substrate 127 and silicon oxide layer 150.Each microchamber 125 of the microfluidic complex is directly above acorresponding heater element 140 to allow the heater to raise thetemperature of the contents of the chamber. (This relationship is shownmore clearly in the cross-sectional end view of the device depicted inFIG. 3).

However, as shown in FIG. 2, the leads 160 (which supply current to theheaters) pass directly beneath microchannel 115. This relationship ismore clearly shown in cross-sectional side view of the device depictedin FIG. 4.

FIG. 4 clearly shows the leads 160 positioned beneath microchannel 115and separated from the channel 115 by only a thin layer of oxide. Thus,the leads 160, when carrying current to heater 140, may warm any fluid(or gas or meltable material) in the microchannel 115, thereby possiblyadversely affecting the operation of the microfluidic device.

Referring again to FIG. 2, the heater leads 160 also run close to thechannels connecting chambers 125 to channel 115. Accordingly, when theleads are supplying electric current to heater 140, they may alsounintentionally warm the contents of any fluid or wax in the sidechannels.

FIGS. 5-7 depict the structure of a first preferred embodiment of theinvention which eliminates, or at least substantially reduces, suchunwanted heat from the leads. In this structure, the resistive heatingelements 540 reside in the oxide layer directly beneath chamber 125,just as they do in the structure shown in FIG. 2. However, unlike thestructure of FIG. 2, the electrical leads do NOT reside in the oxidelayer 150. Rather, as shown in FIG. 6, the leads 565 first pass directlythrough the oxide layer 150 and glass base 130 to the opposite side ofthe substrate 130 (herein “vertical leads”). Preferably the verticalleads 565 are orthogonal to the plane in which heater elements 540reside.

The vertical leads 565 are then connected to horizontal leads 560, whichrun along the opposite side of substrate 130 and connect to terminals570 as shown in FIG. 7. Also as shown in FIG. 7, horizontal leads 560run under channel 115. However, they are now separated from the channelby the full oxide layer 150 and base 130 which act as a thermalisolating layer. Base 130 and oxide 150 should collectively have asufficiently low thermal conductivity to substantially prevent heatemitted by the leads on the bottom of substrate 130 from adverselyaffecting the operation of the microfluidic complex 110. Thus, thisconfiguration substantially reduces the amount of heat transmitted fromthe leads 560 to the microfluidic complex 110.

Those skilled in the art will recognize that the above describedtechnique is not limited to microfluidic devices formed from a pair ofsubstrates, such as shown in FIG. Rather, the technique is generallyuseful in microfluidic devices for reducing unwanted transfer of heatgenerated by the electric leads. Regardless of how the microfluidiccomplex is formed, unwanted heat transfer is reduced if the electricleads are routed from the terminals of the heating element through athermally resistive material, such that the leads are substantiallyisolated from the microfluidic complex.

The vertical leads shown in FIGS. 5 and 6 may be formed by drillingholes through substrate 130 before oxide layer 150 and heater 540 areformed. Typically, such holes are 200-500 μm in diameter, but it shouldbe understood that the size of or method of constructing the hole mayvary. Preferred means for drilling the holes are related to the desireddiameter. For holes 300 μm and greater, mechanical drilling orultrasonic drilling is preferred, although laser drilling also works.Laser drilling presently works for holes as small as 200 μm in diameter;recent research indicates that laser drilling may also work for holes assmall as 50 μm in diameter, or smaller.

Leads 565 may be run through the holes either by electroplating or bysqueezing conductive materials (e.g., pastes) through the holes usingscreen-printing techniques. Materials for electroplating includealuminum, gold, and nickel, as known in the art. Materials forconductive paste include silver-filled epoxy, although other pastes areknown to those skilled in the art to be appropriate.

An alternative method of creating the vertical leads 565 is to form asubstrate that comprises a “grid” of vertical leads, such as shown inFIG. 18. Referring to FIG. 17, such a “lead-gridded” substrate 1810 ispreferably fabricated by stretching a plurality of wires through atabular shaped mold 1710, with the wires spaced in the same spacingdesired for the intended leads. (Alternatively, the leads can be laidout in a rectangular matrix, for example, and the heater leads run tothe nearest pair of vertical leads). Then, a substrate material (such asplastic) is injected into the tube 1710 (or an elongated quadrilateralor another shape appropriate to the method described herein) andsurrounds the wires 1720. The result is a cylinder of substrate materialcomprising wires 1720 that run parallel to the axis of the tube and thatare spaced cross-sectionally as the vertical leads are desired to bespaced in the substrate. See FIG. 17. Then, to obtain a lead-griddedsubstrate, the remaining steps are to slice the cylinder into across-section 1810 of the desired thickness and polish as necessary. SeeFIG. 18. Those skilled in the art will recognize the cost efficiency ofthis method, in that multiple lead-gridded substrates (of uniform orvarying thicknesses) can be obtained from a single wired cylinder of thetype shown in FIG. 17.

Referring to FIGS. 13-15, unwanted heat transfer from the leads to amicrofluidic complex 110 may also be reduced by substantially decreasingthe current density in the leads relative to the current density in theheating elements. In the structure shown in FIGS. 13-15, this isaccomplished by providing the leads with a greater thickness than theconductors of the heater element 540. For example, as shown in FIGS.14,15, the leads 1360 are substantially thicker than the conductor whichforms the heating element 540. Increasing the vertical thickness of thelead wires increases the cross-sectional area of the lead wires, thusdecreasing the electrical resistance of the wires. This also decreasesthe current density within the leads and thereby decreases the amount ofheat radiated by the leads when a given current is applied.

Referring to FIG. 16, heat transfer from the leads to a microfluidiccomplex 110 may also be reduced by increasing the horizontal thicknessof the electric leads 1660 that connect heater elements 540 to a powersource. Here, “horizontal” means in a direction parallel to the plane inwhich oxide layer 150 lies (refer to FIG. 15, for example). The leads1660 have a length taken along a dimension d_(l), which is parallel tothe plane in which oxide layer 150 lies. Leads 1660 are thicker thanheater element 540 along a dimension d_(w),which is parallel to theplane in which oxide layer 150 lies and orthogonal to dimension d_(l),of the leads. The preferred configuration is similar to that shown inFIGS. 2-4. However, the improvement comprised in the embodiment shown inFIGS. 16 lies in the increased horizontal thickness of leads 1660.Increasing the horizontal thickness of the leads increases thecross-sectional area of the lead wires, thus decreasing the electricalresistance of the wires. This in turn decreases the amount of heatradiated by the wires when a given current is applied, thus decreasingthe amount of heat transferred from the wires to microfluidic complex110.

An advantage of increasing the horizontal thickness instead of thevertical thickness is that there is less likely to be a need to increasethe thickness of the oxide layer 150. On the other hand, an advantage ofincreasing the vertical thickness instead of the horizontal thickness isthat a greater number of leads can be used on the substrate withoutinterfering with each other.

In a still further embodiment, the thickness of the leads is increasedin both the horizontal and vertical directions. Those skilled in the artwill recognize that the leads can be modified in a variety of wayswithout departing from the scope of the invention, as long as it resultsin a substantial decrease in the current density within the leads(relative to the current density in the heating elements) to therebyreduce the amount of heat transferred from the leads to the microfluidiccomplex to an acceptable level (i.e., a level that does notsignificantly interfere with the operation of the microfluidic complex).

Other embodiments comprise combinations of the elements above that willbe clear to those skilled in the art. For example, the vertical feedthrough, shown in FIGS. 5-7, can be combined with the thickened leads,(FIGS. 13-16), so that the leads 565 (see, e.g., FIG. 7) that are run“vertically” through the substrate 130 are increased in thickness, tofurther reduce heat emitted by the leads 565 and potentially transferredto the microfluidic complex 110. Similarly, the leads 560 (again, seeFIG. 7) that run along the lower side of substrate 130 can also beincreased in thickness to reduce heat emitted by the leads 560 thatcould be transmitted to the microfluidic complex 110, althoughpreferably the substrate 130 is comprised of material with a thermalconductivity low enough to make such a modification unnecessary.

The amount of heat in a microfluidic complex may also be controlledusing one or more Peltier devices. See FIGS. 8-12. Such devices can bemade to act as heat pumps, removing unwanted heat from a microfluidiccomplex or component thereof. Peltier devices are well-known (see U.S.Pat. No. 5,714,701, to Chi et al., for example). Peltier discovered theeffect that bears his name in 1834. Modem Peltier devices (also known asthermoelectric cooling devices) are typically composed of segments ofheavily-doped semiconductors (often bismuth telluride) that areconnected electrically in series and thermally in parallel between theheated and cooled surfaces of the device. Such devices are availablecommercially, for example, from MELCOR, 1040 Spruce Street, Trenton,N.J. 08648; see also http://www.melcor.com.

In this second preferred embodiment, at least one Peltier device 810 isattached to the substrate 130, although in an alternate embodiment atleast one Peltier device 910 (see FIG. 9) is attached to the uppersubstrate 120 of a preferred microfluidic device. This “upper” Peltierdevice 910 can be in addition or an alternative to any “lower” Peltierdevices 810 attached to the substrate 130. Preferred Peltier devices arebattery-operated, and are attached to substrate 130 or substrate 120using a heat-transfer paste, to improve heat conduction. In thisembodiment, a Peltier device is used to cool an entire microfluidicchip. As discussed below, Peltier devices are used in other embodimentsto cool selected areas of a chip, sometimes cooling different areas atdifferent times, depending on the preferred operation of a microfluidiccomplex in the chip.

Peltier devices are preferably used to remove heat primarily fromselected areas of a microfluidic complex. For example, unnecessary powerconsumption would result if a Peltier device was cooling the entiresubstrate at the same time that a heater element was attempting to heata selected chamber in the substrate. By using a plurality of Peltierdevices, controlled electronically, heat can be removed from selectedareas of a microfluidic complex while allowing other areas to be heatedwith a minimum of consumed power. FIG. 10 shows two Peltier devices 1010attached to the bottom of substrate 130 so as to be capable of coolingselected areas (microchambers 125) of a microfluidic complex insubstrate 120. The depicted configuration is, of course, merelyexemplary—any operable configuration of multiple Peltier devices, wherethe Peltier devices are of any compatible collection of shapes, wouldalso work in this embodiment. Further, although the depictedconfiguration is for a chip with heater leads as in FIGS. 5-7, amultiple-Peltier-device configuration can also be used on a microfluidicdevice such as that depicted in FIGS. 2-4. Multiple Peltier devices 910can be similarly configured on the top substrate 120 of a microfluidicdevice. Peltier devices can be used to cool an entire microfluidic chip,an entire microfluidic complex, or selected portions (channels,chambers, etc.) thereof, and different Peltier devices can be used atdifferent times, depending on desired functionality of the microfluidiccomplex.

FIGS. 11 and 12 depict cross-sectional views of the device in FIG. 10. Asilicon oxide layer 1150 covers heater leads 560. A heat-transfer pastelies between silicon oxide layer 1150 and Peltier devices 1010.

While the operations described above have been for simple designs, thepresent invention contemplates more complicated devices involving theintroduction of multiple samples and the movement of multiplemicrodroplets (including simultaneous movement of separate and discretedroplets), as well as multiple microchannels and microchambers, andpotentially including meltable materials. Furthermore, as discussedabove, those skilled in the art will recognize that the subjectinvention is not limited to microfluidic devices comprised of one glasssubstrate bound to another, or to microfluidic complexes formed byetching or otherwise forming chambers and channels into the bottomsurface of an upper substrate that is then bonded to a lower substrate,or even to microfluidic devices formed by bonding one substrate toanother. The present invention will be recognized by those skilled inthe art as applying to any microfluidic device that comprises amicrofluidic complex having a heating region.

Moreover, although much of the above description depicts, for simplicityof explanation, two leads running from each heater element, it ispossible to share leads among heater elements so that, for example, twoheater elements can be served by three leads (e.g., with the shared leadserving as a common ground).

1. An integrated microfluidic processing system comprising amicrofluidic device, the device comprising: a microfluidic complexcomprising at least one thermally actuated component, wherein at leastone thermally actuated component is configured for moving fluid in themicrofluidic device; a thermally insulating substrate comprising aheating element configured to actuate the thermally actuated component;at least one conductive lead for supplying electrical current from acurrent source to the heating element, wherein the lead has a lowercurrent density that the heating element; and a Peltier coolerconfigured to remove heat from specific regions of the microfluidiccomplex.
 2. An integrated microfluidic system comprising a microfluidicdevice, the device comprising: first and second substrates defining,therebetween, a microfluidic complex; at least one heating elementconfigured to heat a portion of the microfluidic complex, at least oneheating element further configured for moving fluid in the microfluidicdevice; at least one conductive lead for supplying electrical currentfrom a current source to the heating element, wherein the lead has alower current density that the heating element; and one or more Peltierdevices abutting one or both of the first and second substrates.
 3. Thesystem of claim 2, wherein the one or more Peltier devices are attachedto the substrates with a heat-transfer paste.
 4. The system of claim 2,wherein at least one of the Peltier devices is configured to cool theentire microfluidic complex.
 5. The system of claim 2, wherein at leastone of the Peltier devices is configured to cool a specific region ofthe microfluidic complex.
 6. The system of claim 5, wherein the specificregion includes a microchamber in the microfluidic complex.
 7. Thesystem of claim 2, comprising multiple Peltier devices abutting one ofthe first and second substrates.
 8. The system of claim 2, comprisingtwo or more Peltier devices, wherein the two or more Peltier devices areindependently controllable.
 9. The system of claim 2, wherein theheating element is contained within an insulating layer disposed betweenthe first and second substrates.
 10. The system of claim 2, furthercomprising an insulating layer adjacent one of the first and secondsubstrates, wherein at least one of the one or more Peltier devices isattached to the insulating layer.
 11. The system of claim 2, wherein theone or more Peltier devices are controlled electronically, or arebattery operated.
 12. The system of claim 2, further comprising aconductor in electrical communication with the heating element whereinat least a portion of the conductor is separated from the microfluidiccomplex by one of the first or second substrates.